神經纖維瘤第一型病患之軸突興奮性研究

Abstract

神經纖維瘤第一型(neurofibromatosis type1，NF1)是一種常見的神經性遺傳疾病。臨床表徵主要為皮膚色素沉積、神經纖維瘤、骨骼發育缺陷及其他神經、皮膚等症狀。將近40% NF1病患潛藏的叢狀神經根神經織維瘤可能病變為惡性週邊神經纖維髓鞘瘤(Malignant Peripheral Nerve Sheath Tumors;MPNST)。 許多NF1病患具有感覺方面的症狀和神經性疼痛，但其四肢上可以觀察到皮膚神經織維瘤但也可能沒有。臨床上，常見的體感覺誘發電位(somatosensory evoked potential;SSEP)和神經傳導檢查（Nerve conduction study)這兩種方法，但檢查結果通常沒有顯著異常。近年來，神經興奮性檢測(NET)開始被用來評估早期週邊神經系統疾病的電生理特性。NET透過QTRAC program中五個模式(1)刺激-反應曲線、(2)強度-持續時間、(3)閾值電緊張、(4)電流 - 電壓曲線、(5)復原週期，其記錄軸突興奮性的閾值。 本研究針對神經織維瘤第一型病患共92位進行神經興奮性檢查。評估正中神經的運動及感覺軸突之興奮性。首先將NF1病患分為兩類：第一類為有皮膚神經纖維瘤的病患(NF1(skin NF1))，第二類為有叢狀神經根纖維瘤與多發性神經根纖維瘤的病患(NF1(P+C))。透過NET所收集的數據參數分為以下三個群組進行比較分析：正常受試者、Skin NF與NF1 (P+C)。接著將NF1病患所填寫的ID pain疼痛問卷量表中，分數0分與1~5分者分為兩組。在神經興奮性檢查之運動軸突部份，NF1病患與正常受試者相比的變化顯示，NF1病患需明顯較高的電流以達到50% max response、stimulus-response slope 明顯減少、reobase也呈現偏高。而NF1 (skin NF)與NF1 (P+C)則是沒有顯著的差異。而在感覺軸突的研究結果中顯示，NF1病患與正常受試者相比在peak response 有較高的閾值電流、stimulus-response slope的斜率變小、SDTC變大而rheobase變低。閾值電緊張實驗(TE)的結果說明，NF1病患與正常受試者有顯著的差異。TE也顯示了 fanning-in pattern。NF1病患在relatively refractory period (RRP)有明顯的延長、refractoriness 2ms、super- and sub-excitability 閾值的百分比減少。同時運用ID Pain 疼痛問卷量表，評估NF1 病患的感覺方面的症狀表現。並將有症狀(1~5分)進一步與體感覺誘發電位(SSEP)做分析，發現N9-13跟numbness具有相關性。再將NF1病患分為NF1(score0)與 NF1(score1~5)做比較，發現 NF1病患與正常受試者並沒有顯著差異。除了在正中神經運動軸突的superexcitability和正中神經感覺軸突的accommodation half time的參數上具有差異性。 本研究中，我們將 NF1病患分組後進行NET。發現 NF1病患在NET中與正常受試者有顯著差異，但是這些差異與NF1的嚴重程度沒有相關。因為神經纖維瘤是由許旺細胞而來的，並不是受到髓鞘的缺陷或是腫瘤的擠壓，而導致nodal及paranodal regions離子通道的重新分配以及結間區膜內電量的改變。而此兩種異常都會影響NF1病患在NET中參數的結果。

Neurofibromatosis type 1 (NF1) is a common neurological hereditary disorder. The main clinical symptoms include skin pigmentation, neoplasms, body defects and other neurocutaneous manifestations. Nearly 40% of NF1 patients harbor a plexiform neurofibroma which can be transformed into a Malignant Peripheral Nerve Sheath Tumor (MPNST). Many NF1 patients had sensory symptoms and neuropathic pain can be seen in limbs with/without a local skin neurofibroma. The conventional somatosensory evoked potential or nerve conduction studies are usually unremarkable. Recently, nerve excitability test (NET) has been introduced to evaluate the electrophysiological properties in early stage of disease in peripheral nervous system. NET records the axonal excitability threshold using five modes of QTRAC program: 1) stimulation-response curve, 2) strength-duration curve, 3) threshold electrotonus (TE), 4) current-voltage (I/V) curve, and 5) recovery cycle (RC). We have recruited 92 NF1 patients for the study. The excitability of motor and sensory axons of the median nerve was evaluated. There were two subclassifications for the NF1 patients. Firstly, we classified the NF1 patients into NF1 with skin neurofibroma (NF1 (skin NF)) and NF1 with plexiform or Christmas-tree like neurofibroma (NF1 (P+C)). The NET indices from normal control, NF1 (skin NF) and NF1 (P+C) were collected for comparison. In the second part, the NF1 patients had been subdivided into NF1 with ID pain score, 0 and those with score 1~5. The changes in NET indices of motor axons in NF1 patients showed that compared with normal controls, NF1 patients had a significant higher current to achieve the 50% of maximum response, a reduced slope of stimulus-response curve, and a higher reobase. There is no significant difference between the groups of NF1 (skin NF) and NF1 (P+C). In sensory study, NF1 patients had a higher threshold current in peak response, a lower slope of stimulus-response curve, a higher SDTC and a shorter reobase as compared with controls. The threshold-electrotonus study demonstrated that NF1 patients had a significant index changes as compared to controls. The TE study showed a fanning-in pattern. NF1 patients showed a significant increase of relatively refractory period (RRP), a reduced refractoriness at 2 ms, and a reduced super- and sub-excitability. The questionnaire of ID pain has been collected to evaluate the sensory symptoms in NF1 patients. The patients with score 1~5 and numbness had a prolong latency of N9-13 in SSEP. While subclassified the NF1 patients into NF1 (score 0) and NF1 (score 1~5), there were no significant difference among the NF1 patients and controls, except the superexcitability in median motor axons and the accommodation half time in median sensory axons. In the study, we subclassified the NF1 patients and compared the NET indices. NF1 patients had a significant change in NET indices as compared to controls, but the change did not correlate with the disease severity. Since neurofibroma is derived from Schwann cells, either a defect in myelin formation or a tumor compression would result in ion-channel redistribution at nodal or paranodal regions and/or changes in membrane capacity at internodal area. Both abnormalities have impacts on the changes in NET indices of axons from NF1 patients.